This invention is in the field of chemical restructuring of pharmaceutical agents known to cause toxicity or adverse drug reactions in noncancerous tissues as a side effect, by producing their orotate derivatives. More particularly, it concerns derivatives of the anthracyclines, doxorubicin and daunorubicin, that are used as anticancer drugs.
The antibiotic doxorubicin (DOX) and its salts, as well as other cationic anthracyclines currently are of great clinical interest in the treatment of cancer, including leukemias and solid tumors. Great hopes have centered on the use of liposomes as transport systems for bioactive agents. It has been established that the use of liposomes for the administration of anti-neoplastics in many cases improves the traditional methods of administration. Gabizon et al, Cancer Res. (1982), 42; 4234-4739 and Van Hossel et al, Cancer Res (1984) 44; 3698-3705. Different patents describe the inclusion of anti-free radical agents into liposomes having improved activity as inhibitors of lipid peroxidation. U.S. Pat. No. 5,605,703, issued Feb. 25, 1997. Liposomal encapsulation can substantially affect a drug's functional properties relative to those of the unencapsulated drug. In addition, different liposomal drug products may vary from one another in the chemical composition and physical form of liposomes. Such differences can substantially affect the functional properties of liposomal drug products. Doxyrubicin HCl which is the established name for (85, 105)-10-[(3-amino-2,3,6-trideoxy-(c-L-lyxo-hexopyranosyl) oxy]-8-glycolyl 1-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula of the drug is C27H29NO11HCl; its molecular weight is 579.99.
DOXIL® (doxorubicin HCl injection) is doxorubicin hydrochloride (HCl), encapsulated in STEALTH® liposomes used for intravenous administration. The STEALTH® liposomes of DOXIL® are formulated with surface-bound methoxypolyethlyene glycol, a process often referred to as pegylation, to protect liposomes from detection by the mononuclear phagocyte system and to increase blood circulation time.
STEALTH® liposomes have a half-life of approximately 55 hours in humans. They are stable in blood, and direct measurement of liposomal doxorubicin shows that at least 90% of the drug remains liposome-encapsulated during circulation.
Experience with DOXIL® at high cumulative doses is limited and therefore it is assumed that DOXIL® will have myocardial toxicity similar to conventional formulations of doxorubicin HCl. Irreversible myocardial toxicity leading to congestive heart failure often unresponsive to cardiac support therapy may be encountered as the total dosage of doxorubicin HCl approaches 550 mg/m2. Swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic reactions have been reported.
Doxorubicin has been successfully administered by a wide range of schedules, and the anti-tumor activity of doxorubicin is proportional to the area under the concentration×time curve (AUC) not to peak drug levels. The AUC for concentrated doxorubicin HCl is 9.9 mg/ml-h. The AUC (mg/ml-h) for DOXIL® is 590.
Cardiac Toxicity—The cardiac toxicity exhibited by doxorubicin and the other anthracyclines is unique in terms of its pathology and mechanism. The major limiting facts in the clinical use ofanthracylclines in adults are bone marrow suppression, mucositis, and drug resistance on the part of the tumor. However, in individual patients, most commonly with the use of doxorubicin to treat breast cancer, cardiac toxicity can develop while the patient's tumor is still responsive to the drug. This is a problem not only for the use of the anthracyclines alone or in combination with other chemotherapeutic agents but also for the use of the monoclonal antibody trastuzumab and an antibody directed against HER2/neu oncoprotein, which is itself active in the treatment of advanced breast cancer. The observed potential of anthracycline-induced heart damage by trastuzumab has eliminated its use with doxorubicin in the population of patients whose tumors exhibit high levels of HER2/neu expression. Children seem to be more sensitive to the cardiac toxicity of this drug, and this has become a significant problem in the use of doxorubicin in pediatric oncology. Management of Drug Toxicity, Ch 31-42, in The Chemotherapy Source Book, 3rd ed, Michael C. Perry, Lippincott Williams & Wilkins, 2001.
Thus there is a great need for analogues which give a better rate of response, a wider spectrum of response, and/or reduce cardiotoxicity. Halogenated anthracyclines, mechanistically different from doxorubicin and daunorubicin, have been produced. In particular, derivatives that have fluorine groups attached to their sugar moieties have a strong ability to kill tumor cells. Much of the history and prior art of doxorubicin is found in issued patents and published literature. See U.S. Pat. Nos. 5,304,687 issued Apr. 19, 1994; 5,605,703 issued Feb. 25, 1997; U.S. Pat. No. 6,210,930 issued Apr. 3, 2001; U.S. Pat. No. 6,284,737 issued Sep. 4, 2001; and U.S. Pat. No. 6,653,455 issued Nov. 25, 2003.
However, the present invention is distinguishable from the prior art because none of the prior art addresses the issue of preventing and/or reducing the levels of drugs in noncancerous tissues, as a strategy to reduce the toxicity and adverse drug reactions. More effective and less toxic agents are widely sought and are a fundamental object of the invention. The pertinent subject matter of the above references is specifically incorporated herein by reference.